Intracardiac injection of erythropoietin induces stem cell recruitment and improves cardiac functions in a rat myocardial infarction model

• Published in: Journal of cellular and molecular medicine 2009-04, Vol.13 (4), p.664-679
• Main Authors: Klopsch, Christian, Furlani, Dario, Gäbel, Ralf, Li, Wenzhong, Pittermann, Erik, Ugurlucan, Murat, Kundt, Guenther, Zingler, Christiana, Titze, Ulf, Wang, Weiwei, Ong, Lee‐Lee, Wagner, Klaus, Li, Ren‐Ke, Ma, Nan, Steinhoff, Gustav
• Format: Article
• Language: English
• Subjects: AKT protein; Animals; Apoptosis; Apoptosis - drug effects; c-Kit protein; cardiac regeneration; Catheters; CD34 antigen; Cell Survival - drug effects; chemoattractant; Chemokine CXCL12 - metabolism; Comparative analysis; Coronary vessels; Disease Models, Animal; Erythropoietin; Erythropoietin - administration & dosage; Erythropoietin - pharmacology; Erythropoietin - therapeutic use; Heart; Heart attacks; Heart Function Tests; Hematocrit; Hematology; Hematopoietic Stem Cell Mobilization; Humans; Hypoxia; Injection; Injections; Intubation; ischaemia; Ischemia; Matrix Metalloproteinase 2 - metabolism; Monoclonal antibodies; Myocardial infarction; Myocardial Infarction - drug therapy; Myocardial Infarction - enzymology; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardium; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Neovascularization, Physiologic - drug effects; Peripheral blood; Polyclonal antibodies; Rats; Receptors, CXCR4 - metabolism; Receptors, Erythropoietin - metabolism; Recombinant Proteins; Rodents; SDF-1 protein; Software; stem and progenitor cells; Stem cells; Troponin T - metabolism; Up-Regulation - drug effects; Veins & arteries; Ventricle
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/j.1582-4934.2008.00546.x

Erythropoietin (EPO) protects the myocardium from ischaemic injury and promotes beneficial remodelling. We assessed the therapeutic efficacy of intracardiac EPO injection and EPO‐mediated stem cell homing in a rat myocardial infarction (MI) model. Following MI, EPO (3000 U/kg) or saline was delivered by intracardiac injection. Compared to myocardial infarction control group (MIC), EPO significantly improved left ventricular function (n= 11–14, P< 0.05) and decreased right ventricular wall stress (n= 8, P< 0.05) assessed by pressure‐volume loops after 6 weeks. MI‐EPO hearts exhibited smaller infarction size (20.1 ± 1.1%versus 27.8 ± 1.2%; n= 6–8, P< 0.001) and greater capillary density (338.5 ± 14.7 versus 259.8 ± 9.2 vessels per mm; n= 6–8, P< 0.001) than MIC hearts. Direct EPO injection reduced post‐MI myocardial apoptosis by approximately 41% (0.27 ± 0.03%versus 0.42 ± 0.03%; n= 6, P= 0.005). The chemoattractant SDF‐1 was up‐regulated significantly assessed by quantitative realtime PCR and immunohistology. c‐Kit+ and CD34+ stem cells were significantly more numerous in MI‐EPO than in MIC at 24 hrs in peripheral blood (n= 7, P< 0.05) and 48 hrs in the infarcted hearts (n= 6, P< 0.001). Further, the mRNAs of Akt, eNOS and EPO receptor were significantly enhanced in MI‐EPO hearts (n= 7, P< 0.05). Intracardiac EPO injection restores myocardial functions following MI, which may attribute to the improved early recruitment of c‐Kit+ and CD34+ stem cells via the enhanced expression of chemoattractant SDF‐1.